Metastatic melanoma is almost uniformly fatal due to the development of resistance to all treatments. While recent FDA-approved drugs are achieving blockbuster status (e.g., Zelboraf), life expectancy is increased by just months and side effects are severe. While the commercial potential of radionuclide therapy is evidenced by recent introductions (e.g., Xofigo), the approach has yet to be introduced for metastatic melanoma. In this proposal, we determine the feasibility of a novel combination image-guided radionuclide therapy for metastatic melanoma using our new [203/212Pb]-labeled products (DOTA-VMT-MCR1 and DOTA-RMX-GC), which target melanoma specific molecular targets with high affinity and specificity. In the proposed research, we will determine the commercial feasibility DOTA-VMT-MCR1/DOTA-RMX-GC as separate ligands and as multireceptor- targeted hybrids that target MCR1/GLUT simultaneously for image-guided radionuclide therapy. The objective of this Phase I SBIR is to: (1) Determine the feasibility of radiosynthesis of [212Pb]DOTA-RMX-GC and [212Pb]DOTA-VMT-MCR1 using two available 212Pb generators; (2) Evaluate the feasibility of [212Pb]DOTARMX- GC and [212Pb]DOTA-VMT-MCR1 therapy in melanoma-tumor-bearing mice; and (3) Determine the feasibility of a dual-targeted (GLUT1/MCR1) bioconjugate for radionuclide imaging and therapy for metastatic melanoma. With success in these aims, we expect to advance our compounds through risk-mitigating milestones toward submission of new drug applications and clinical trials.